WO2013156088A1 - Pastilles à teneur élevée en principe actif - Google Patents

Pastilles à teneur élevée en principe actif Download PDF

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Publication number
WO2013156088A1
WO2013156088A1 PCT/EP2012/059196 EP2012059196W WO2013156088A1 WO 2013156088 A1 WO2013156088 A1 WO 2013156088A1 EP 2012059196 W EP2012059196 W EP 2012059196W WO 2013156088 A1 WO2013156088 A1 WO 2013156088A1
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WIPO (PCT)
Prior art keywords
pellets
granules
active ingredient
spraying
liquid
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Application number
PCT/EP2012/059196
Other languages
German (de)
English (en)
Inventor
Monika Cwik
Herbert Hüttlin
Original Assignee
Acino Pharma Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Acino Pharma Ag filed Critical Acino Pharma Ag
Priority to EP12722352.7A priority Critical patent/EP2838514A1/fr
Publication of WO2013156088A1 publication Critical patent/WO2013156088A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/603—Salicylic acid; Derivatives thereof having further aromatic rings, e.g. diflunisal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/16—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by suspending the powder material in a gas, e.g. in fluidised beds or as a falling curtain
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
    • B29B9/00—Making granules
    • B29B9/16—Auxiliary treatment of granules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
    • B29B9/00—Making granules
    • B29B9/16—Auxiliary treatment of granules
    • B29B2009/166—Deforming granules to give a special form, e.g. spheroidizing, rounding

Definitions

  • the present application relates to pellets containing at least one active substance, as well as processes for pellet production and medicaments containing the pellets according to the invention.
  • the pellets are obtainable by spraying active ingredient-containing granules with a solvent for the active ingredient or with a liquid containing active substance.
  • an outdoor area can be generated, which differs structurally and / or materially from the sprayed granules. This outer area, the longer the spray time the more clearly appear as the actual drug-containing "coating layer" in appearance.
  • the pellets of the invention are small and are characterized by a high content of active ingredient and a favorable release behavior. The latter can u.a. can be achieved by cavities present in the granules according to the invention. Despite these cavities, the pellets according to the invention have the required breaking strength.
  • Pellets of different construction and produced by various methods are known from the literature. Whereas, for example, matrix pellets produced by extrusion / spheronization have a homogeneous structure, it is possible to distinguish between a core and a cladding layer in the case of pellets produced by coating. They are therefore called heterogeneous pellets.
  • a commonly used method of pellet preparation is based on inert cores ("nonpareilles"). These inert cores are sprayed with a solution of an active ingredient and a binder, or with a powder mixture of active ingredient and excipients, so that a coating of the inert core takes place.
  • spherical cores makes it possible to easily obtain pellets which have excellent roundness since the roundness is ultimately determined by the roundness of the inert core.
  • a round pellet shape is advantageous in many ways. If, for example, the pellets are to be provided with an enteric coating or another coating, the smaller surface area of a round pellet mold can reduce the amount of coating material to be used and it can produce a more even coating 2
  • Layer thickness of the coating material can be achieved. Furthermore, round pellets have better flowability and the absence of edges can be e.g. also reduce the abrasion.
  • the drug loading should be as high as possible.
  • the coating of pellet cores with solutions or suspensions is less suitable because long process times and a high energy expenditure for evaporating the liquid are required.
  • the process time can be significantly shortened by powder coating.
  • the problem with powder coating is undesirable agglomeration of the product and adhesion to surfaces such as e.g. on the container walls. Since the tendency to agglomerate decreases with increasing particle size and the flow properties are better, often relatively large starter cores (> 500 ⁇ ) are used.
  • Particles without inert starter cores can be produced, for example, by extrusion processes and subsequent spheronization. This is a relatively expensive process. Since different and special apparatuses are required for carrying out the individual method steps, the method is complex and expensive compared to other methods.
  • a moist mixture of an active ingredient with a suitable auxiliary agent is first pressed through defined pressing channels, the length of which results in varying extrudates, also called extrudate strands.
  • extrudate strands the strand diameter of the extrudates is limited, whereby the size of the particles to be produced by extrusion and subsequent spheronization down is limited. In the spheronization process, the extrudate strands break into shorter fragments, which will be rounded below.
  • the fragments must have sufficient plasticity, which makes the addition of larger amounts of microcrystalline cellulose (MCC) to the mass to be extruded required for many pharmaceutical agents.
  • MCC microcrystalline cellulose
  • the high proportion of excipients prevents the production of particles with high active ingredient content.
  • EP 1 020 181 A1 which deals with particles produced by extrusion and spheronization with so-called high active ingredient content, states that the proportion of a mixture of MCC with hydroxypropyl cellulose is preferably 20-30% by weight of the active substance to be extruded - Mix should be.
  • Sphericities are not specified in EP 1 020 181 A1. Particles which are produced by extrusion and subsequent spheronization have no active substance-containing coating layer.
  • Another process for producing pellets are granulation processes. It can e.g. Intensive mixer, fluidized bed equipment or rotor granulators are used, wherein the manufacturing process resp. the design of the granulator influences the structure of the product obtained.
  • the granulation in the rotor granulator resulted in a better active ingredient distribution and higher bulk density of the granules produced at a lower active ingredient content than in a conventional fluidized bed apparatus (Kristensen J, Hansen VW; Wet Granulation in Rotary Processor and Fluid Bed: AAPS PharmSciTech 7, art. 22 (2006)).
  • particles produced in the rotor granulator were rounder and had a smoother surface (Pisek R, Kroselj V, Vrecer F, Comparison of direct rotor pelletization (fluidbed) and high-shear pelletization method for pellet production, Pharm Ind 67, 243-248 (2005)).
  • Kernels also found that compared to pellets made in the rotor granulator, the surface of pellets made in the top-spray process (spraying the material from above) in fluid bed equipment was rough, the pellets were smaller, and the measured content and yield were lower. This was attributed to spray-drying effects and agglomeration in the top-spray process.
  • US 5,476,667 describes e.g. a melt granulation process in an intensive mixer. It works with a powder mixture containing the active ingredient and a relatively low-melting thermoplastic component, so that forms by melting this component during the process, a plastic mass.
  • sphericity values of the particles produced are not mentioned.
  • a disadvantage of the melt granulation process is that the choice of thermoplastic ingredients is limited because they must have a relatively low melting point. Because of the elevated temperatures necessary to melt the thermoplastic component during the process, temperature sensitive drugs can not be processed by melt granulation.
  • US 5,476,667 also indicates the need for the active ingredient used in this process to be cohesive.
  • 6,264,989 B1 in Example 4 describes the production of vitamin C particles and starts thereby from large vitamin C crystals (particle size 180-355 pm). These are coated in a first coating step in a first apparatus (CF-Granulator®) with powdered vitamin C (particle size 21, 4 pm) while water is sprayed at the same time. In a further coating step, the resulting particles are then sprayed with a vitamin C-containing solution in a second apparatus (Flow Coater®). The resulting particles are characterized by their core of a large crystal. The method is complicated insofar as that vitamin C is required in two different particle sizes and the first apparatus must have two nozzles to accomplish the dispensing of the powdered vitamin C as well as the spraying of water in the first process step.
  • Veccio et al. discloses that even 30% MCC is necessary to pellets containing Indobufen on a rotor granulator MP 1 (Niro-Aeromatic, Bubendorf, Switzerland) of good quality. From an active-containing coating layer Veccio et al. otherwise not.
  • a pellet production process which seeks to dispense with MCC is described in EP 1 333 812 B1.
  • microgranules having a high active ingredient content consisting of a granule forming a core and a cladding layer are produced.
  • the core, the microgranules described in EP 1 333 812 B1 is produced by wet granulation in a Glatt GPCG1 apparatus equipped with a so-called "bottom spray tank”.
  • the granules are then wrapped in a second process step, including a binder and active ingredient-containing suspension (ie no solution) is sprayed.
  • a very thick coating layer is sprayed onto the nucleating granules to ultimately produce microparticles with good sphericity.
  • the proportion of the weight of the coating layer in the total weight of the pellets in the examples of EP 1 333 812 B1 clearly outweighs the proportion by weight of the core-forming granules in the total weight of the pellets.
  • unfavorably long process times are necessary for the application of the thick coating layer.
  • the pellets are said to have high fracture toughness, low abrasion, large batch homogeneity, narrow particle size distribution and constant bulk density.
  • the pellets should have a favorable release behavior of the active ingredient in an aqueous or at least moist medium (such as the stomach or intestine).
  • a process has now been found with which granules containing active ingredient can be produced in a special rotor granulator, which contain a very high proportion of active ingredient and which are already so round that only a very thin active ingredient-containing coating is required to pellets containing active ingredient provide high levels of active ingredient which have excellent roundness, although they need not contain any spherulizing agents such as microcrystalline cellulose. Because the active ingredient-containing coating, which is located on the granules, is very thin, the pellets can be produced with very short process times.
  • the pellets produced by this novel process have structural features which make them distinguishable from known pellets and from pellets made by known processes.
  • the surface of pellets made by powder coating in known processes is e.g. rough, while that of the pellets according to the invention is smoother.
  • a coating a round shape, a low surface / volume ratio, smooth surface, narrow particle size distribution and sufficient hardness are advantageous.
  • Pellets produced by powder coating in known processes also show marked structural differences with respect to the pellets according to the invention, which is evident by their layered structure, whereas the structure of the pellets according to the invention is rather disordered and the pores are more irregularly distributed and larger.
  • MCC-free, yet very round and unbreakable granules can be prepared by using a granulator whose bottom is designed as a fan, the granulation liquid preferably not continuously but discontinuously is sprayed. As a result, for example, material loss is avoided by sticking to container walls.
  • pellets according to the invention are then obtained by spraying the active ingredient-containing granules prepared according to the invention with a solvent for the active substance or with an active substance-containing liquid.
  • break-resistant pellets are obtained with a particularly high active ingredient content and favorable release behavior.
  • These pellets can in many cases be obtained by spraying the granules with a solvent or liquid containing no binder.
  • vorable release behavior may mean that the drug is released very rapidly at the target site. In some embodiments, “favorable release behavior” may mean that part of the drug is released very rapidly immediately after reaching the target site, and that the drug release subsequently slows down substantially or negligibly.
  • the target site is by definition not the stomach. If an optional active agent-free coating of the taste masking of an active substance present in the pellet is used, the destination is not the oral cavity. In the presence of a coating, “favorable release behavior” does not necessarily mean that the drug is released very rapidly at the target site.
  • vorable release behavior in the presence of a retarding layer may mean that the time course of drug release is determined only or almost exclusively by the retarding layer.
  • vorable release behavior may mean that the drug is released in a predominantly aqueous environment within a medically / pharmaceutically desirable period of time after reaching the target site.
  • the coating layer can be very thin.
  • the sheath may also be present only in places, and thus form no continuous sheath layer.
  • short spraying times are preferred during the subsequent spraying with solvent for the active ingredient or with active ingredient-containing liquid, since the process times can thereby be considerably shortened.
  • short spraying times are only possible if the granules are already sufficiently round before being sprayed. There is no teaching in the prior art for producing highly active granules which are sufficiently round, contain no starter core free of active ingredient and have an active substance content of 80% by weight or more.
  • the proportion by weight of the granules forming the core of the pellets according to the invention in the total weight of the pellets can be very high, since the granules forming the core already have a good roundness.
  • no cladding layer of large thickness needs to be formed, e.g. to make a round pellet from a "square" core.
  • the high-active-ingredient-containing pellet of the present invention because of its construction, can be produced in processes with reduced process times (no long production of a thick coating layer) and without the need for various equipment.
  • the present application thus relates, in a first aspect, to a process for the preparation of an active ingredient-containing granulate, which process comprises introducing at least one active ingredient and optionally one or more auxiliaries as a material to be moved into a granulator and granulating it as a treatment medium using a granulation liquid, as a granulator a
  • a device comprising a stationary container (12) having a process chamber (46) in which a bottom (42) rotatable about a vertical axis (32) is arranged, wherein process air (106) between an outer periphery of the rotatable bottom (42) and the surrounding wall (38) of the container (12) into the process chamber (46) is insertable, and has a nozzle for spraying a treatment medium in the process chamber (46) Good (44), characterized in that the bottom (42) is designed as a fan (50, 140) which has a primary fan blade (52, 142) facing the process chamber (46), on the underside of which fan blades (66) are arranged,
  • treatment medium liquids that are sprayed during one or more of these processes.
  • a granulation liquid is sprayed as the treatment medium.
  • an active substance-containing liquid as the treatment medium onto the resulting aggregates (active ingredient-containing granules) or a solvent for the active ingredient contained in the granules.
  • the described granulator may also be referred to as a device for treating particulate material.
  • good particles in the present invention, depending on which process step is carried out to be granulated particles comprising To understand drug particles and optionally one or more excipients, resulting aggregates, granules or pellets.
  • process step is carried out to be granulated particles comprising To understand drug particles and optionally one or more excipients, resulting aggregates, granules or pellets. The following three paragraphs are taken from DE 10 2010 052 312.7.
  • the measure of the formation of the rotating floor as a fan with a fan chamber facing the process chamber has the advantage that the floor is additionally used for process air guidance.
  • the process air can be selectively fed to the annular inlet opening between the outer peripheral edge of the fan and the container wall surrounding it at a distance.
  • the direction, the speed, ie in particular the amount, of the supplied process air can be easily controlled. This contributes to a defined movement of the Gutteilchen upwards.
  • the particles of good are moved upwards exactly by the process air. It is at the same time imposed a circumferential and inward movement component.
  • the good particles are moved helically upwards. The particles then fall due to gravity and these components of motion relatively evenly distributed in the inner process chamber space again in the direction of the bottom, so the fan blade down.
  • Such an annular gap nozzle has a wrap angle of 360 °, d. H. it sprays viewed from the central vertical axis of the treatment medium radially outward, over the entire circumference.
  • This Sprühflade can be thought of as a kind of floating pancake over the rotating fan blade.
  • Fig. 1 is a vertical section of an embodiment of a rotor granulator device as characterized above (hereinafter referred to as "device");
  • FIG. 2 shows the area bounded by a dashed rectangle in FIG. 1 to a greatly enlarged extent
  • Fig. 3 shows the section of Figure 2 in an operation of the device with the corresponding explanations of the flow of the process air and the movements of the goods.
  • Fig. 4 is a sectional view of Fig. 1 with the device in operation in the treatment of good, the Gutoniaen, the process air flow and the effect of a filter powder recirculation system are shown.
  • Fig. 5 is a comparable to Figure 3 representation of a second embodiment of the fan.
  • a first embodiment of the device is shown, which is designated in its entirety by the reference numeral 10.
  • the device 10 has a standing container 12.
  • the container 12 has a central double-walled cylindrical portion 14, which is closed at the upper end with a filter dome 16. From Filterdom 16 is an exhaust port 18 is laterally.
  • a filter / powder recycling system 20 is arranged in the area of the filter dome 16 and in the upper area of the cylindrical portion 14 of the container 12.
  • This system 20 includes filter bags 22 which depend downwardly from a carrier 21. Over the upper end of the filter bags 22 at the level of the carrier 21, a rotating blast shoe 24 is arranged, which is offset by a drive motor 26 in a rotational movement about the central vertical axis 32 of the device 10. Blowing air 29 can be introduced into the interior of the rotating blower shoe 24 via a lateral blower neck 28. The operation will be described later in connection with Figure 4 in more detail. In the filter dome 16 also sits a cleaning nozzle 30, which serves at least this area of the device 10th
  • a product container 34 is arranged at the lower end of the cylindrical portion 14.
  • a laterally inclined from the product container 34, downwardly inclined filling / emptying nozzle 36 serves for filling or emptying of the product container 34th
  • This filling / emptying nozzle 36 opens into a lower wall 38, which represents a continuation of the inner wall of the container 12.
  • the wall 38 has a downwardly and inwardly curved portion 40 which terminates approximately in a horizontal plane and a central central opening 41 surrounds.
  • a bottom 42 is used, on which comes to be treated Good 44, which was introduced through the filling nozzle 36, comes to rest.
  • the interior of the container 12 above the bottom 42 constitutes a process chamber 46.
  • the bottom 42 is designed as a fan 50, as can be seen in particular from FIG. 2 in detail.
  • the fan 50 has a first or primary fan blade 52 which is connected to a shaft 54 extending in the vertical axis 32.
  • the shaft 54 of the fan 50 is rotatably received in a bearing 56, which in turn is mounted in a wind house bottom 58.
  • the wind house bottom 58 forms a lower end of the container 12.
  • the space between wind house bottom 58 and bottom 42 is commonly referred to as a wind house, as in this wind house via a laterally projecting supply air pipe 104, the process air 106 is supplied.
  • Fig. 1 From Fig. 1 it can be seen that the lower end of the shaft 54 of the fan 50 is connected via a belt 62 to a drive motor 60. As a result, the fan 50 can be rotated about the vertical axis 32.
  • curved fan blades 66 which are partially connected to a cover piece 68 in a radially central region of the underside, are arranged on the underside 64 of the first fan blade 52.
  • this cover piece 68 is designed and arranged so that it represents an extension of the inwardly bent portion 40 of the wall 38, as it were.
  • the fan blades 66 are therefore covered on the underside in the radially outer region by the portion 40 and in the radially further inner region by the cover 68.
  • a suction port 70 between the radially inner end of the Abdeck Huaweies 68 and the outside of the shaft 54 remains free. Process air is sucked in via this intake opening 70, as will be described in more detail later, and when rotating Fan 50 of a blowout 72 is supplied.
  • the exhaust opening 72 is an annular opening which opens in the direction of the inner wall 38 of the container 12.
  • an upper, second fan blade 74 is mounted in the fan 50.
  • This second fan blade 74 also has a shaft 76 which projects downwards along the vertical axis 32.
  • This shaft 76 of the second fan blade 74 is mounted in a central central opening 78 of the shaft 54 of the first fan blade 52.
  • a bearing 80 between the outside of the shaft 76 and the inside of the opening 78 in the first shaft 54 allows a relative rotational movement between the first fan blade 52 and second fan blade 74th
  • an opening 84 is provided in the first fan blade 52, approximately at the level of the radially inner end of the cover piece 68, via which process air can be introduced into a gap 82 between the fan blades 52 and 74.
  • This gap 82 opens approximately at the level of the blow-out opening 72. As explained later, thus parts of the process air can be transported through the gap 82 between the fan blades 52 and 74.
  • the first fan blade 52 seen radially from the inside outwards, a first, gently downwardly inclined portion 86 which merges via a gentle curvature in a gently rising end portion 88.
  • the upper, second fan blade 74 has the same geometry.
  • the top 75 and the corresponding surface of the second fan blade 74 thus represents the actual soil on which the good comes to rest.
  • the above-described geometry in the manner of a hat brim promotes a gentle radial transport movement of the goods lying thereon, as will be described in more detail below in connection with FIG. 3.
  • a stationary annular gap nozzle 90 is inserted in the central central opening 78 of the shaft 54 of the first fan blade 52.
  • the shaft 76 of the second, upper fan blade 74 has a central central opening.
  • the annular gap nozzle 90 has an elongated rod-shaped body which extends completely through the shaft 54. At the upper end, the annular gap nozzle 90 has a head which is closed off by a cone 99. There is also the mouth 100 of the annular gap nozzle 90, which sprays about a complete wrap angle of 360 ° approximately horizontally. Inside, two spray air gaps 96, 97 are provided which circumscribe an intermediate liquid gap 98. A liquid moved through the liquid gap 98 to the mouth 100 is atomized to a fine spray mist by the spray air emerging on both sides via the spray air gaps 96 and 97. Due to the geometry with the 360 ° wrap angle exits from the mouth 100, an approximately flat Sprühflade 101, as indicated in Fig. 3 and 4.
  • Each spray jet emerging from a gap has a continuously widening spray cone 102, this is also the case with the spray bloom 101, ie. H. each further radially outward one considers the Sprühflade in vertical section, the further the cone 102 has widened.
  • the orifice 100 is spaced slightly above the uppermost radially inner end of the second fan blade 74, so that it is possible for this spray cone 102 to form.
  • annular gap nozzle 90 is connected at its lower end with a corresponding supply 108, via which the various media, ie spray air and spray liquid can be supplied.
  • orifice 100 is oriented such that the sprayed filament 101 extends approximately in a horizontal plane.
  • blow gap 94 is formed between the outer side 92 of the rod-shaped body of the stationary annular gap nozzle 90 and the opening 78 in the shaft 54 or in the shaft 76.
  • this blow gap 94 is supplied with blown air by a laterally projecting blow gap supply 110.
  • This blown air is guided from bottom to top in the blow gap 94 and, as can be seen in particular in FIG. 3, exits briefly below the mouth 100.
  • This blown air can be used to blow the mouth 100 free from any caking and accumulation of material during operation. It is known that in the immediate mouth region of an orifice 100 laterally negative pressure areas are created in which flying particles or liquid droplets are sucked in, which then adhere to this area and, due to the usually sticky treatment materials, tend to form caking. This can be absolutely avoided by this construction.
  • This blowing air can serve to support the lower end of the Sprühflade 101, as shown in Fig. 3 can be seen.
  • Fig. 3 and 4 is shown how the process air ducts and the Play or behave movement of the material to be treated in the device 10 according to the invention. After filling through the filling nozzle 36, the material is initially on the top, so the second fan blade 74th
  • the fan 50 and thus the first fan blade 52 are offset by the drive motor 60 in a rotational movement about the vertical axis 32.
  • By appropriately rubbing training of the bearing 80 and the second, uppermost fan blade 74 is rotated, but at a lower speed.
  • Process air 106 is introduced into the wind house via the laterally projecting supply air stub 104, and this flows to the intake opening 70 of the fan 50.
  • the fan blades 66 move the process air 106 in the direction of the exhaust opening 72.
  • a portion of the process air 106 is introduced via the opening 84 in the gap 82 between the lower, first fan blade 52 and the upper, second fan blade 74, and this flows to the radially outer orifice in the region of Blow-out opening 72.
  • the amount of process air contained in this gap 82 can also be used to control the relative speed between the first fan blade 52 and the second fan blade 74. If a lot of process air 106 introduced into the gap 82, this increases the friction between the motor-driven lower, first fan blade 52 and the freewheeling mounted second fan blade 74.
  • the speed of the upper, second fan blade 74 thus depends on the friction of the bearing 80 and the corresponding here unspecified seals, the height of the gap 82 and the supplied in this space process air quantity.
  • the material received in the product container 34 is, as can be seen in particular in FIG. 4, moved vertically upwards along the inside of the wall 38 of the container 12 by the process air 106 emerging from the outlet opening 72.
  • the soil particles 44 present on the ground initially move radially downwards over the first, downwardly inclined portion 86 ', are then guided somewhat upwards by the rising end portion 88', the movement being directed upward through the curved portion 40 of FIG Wall 38 gently takes place, so this Good particles 44 from the horizontal movement gently, but nevertheless very quickly and effectively deflected in the vertically upward movement.
  • the gut particles 44 are additionally imposed a circumferential component, so that they perform an orbital-toroidal space movement.
  • the good particles 44 When falling down, the good particles 44, as shown in FIGS. 3 and 4, now strike the spray discharge 101, which is sprayed approximately horizontally, and they are thereby subjected very uniformly to the spray medium to be treated.
  • the Gutteilchen 44 After passing through the Sprühflade 101, the Gutteilchen 44 impinge on the top 75 of the upper second fan blade 74. It has been found that at a relatively low speed of the second fan blade 74, the Gutteilchen 44 are placed in a kind of rolling motion, as indicated by the arrows. 1 12 is shown.
  • the Gutteilchen 44 roll relatively gently, so injury, radially outward and are gripped by the process air 106 and moved upwards. In this area, they enter into an exchange with the heat of the process air so that the sprayed-on medium can dry off.
  • the second embodiment of a fan this is designated in its entirety by the reference numeral 140. Again, it is so that many components of the fan 140 are the same as the components of the fan 50 described above, so that in this respect again the same reference numerals are used.
  • the fan 140 has only a single fan blade 142, on the underside of the fan blades 66 are mounted. Again, the shaft 54 is provided, via which the fan 140 is rotatably received in the bearing 56. Here, too, a standing annular gap nozzle 90 is inserted into the central central opening of the shaft 54.
  • process air 106 is introduced laterally between the underside of section 40 of wall 38 and the windbox floor 58, and this flows via the fan blades 66 to a blowout port 147.
  • the fan blade 142 is rotated about the vertical axis. This rotational movement can, as described above, be effected by a drive. This rotational movement can also be generated exclusively by the process air 106.
  • the method according to the invention for the preparation of active ingredient-containing granules comprises the use of the device as a granulator, as claimed in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 and / or 15 of the patent application DE 10 2010 052 312.7 is described. These embodiments are incorporated herein by reference.
  • the granules produced according to the invention comprise a large number of granules.
  • the term Granule is used according to the invention for a single granule, which is an aggregate of powder particles.
  • Powder particles may include drug particles and optionally adjuvant particles, e.g. Flow agent particles, be.
  • the active ingredient particles are typically active ingredient crystals, active ingredient powder and / or partially crystalline or amorphous or glassy active substance particles.
  • the granule does not comprise an active substance-free starter core.
  • active substance on the one hand means a substance which is administered to exert a pharmacological action in the broadest sense in or on the living human or animal body (hereinafter referred to as pharmaceutical active substance).
  • active substance but also substances to be understood, which are administered for diagnostic purposes or as a dietary supplement.
  • vitamins are considered as dietary supplements.
  • the process according to the invention for the production of an active ingredient-containing granulate relates to the preparation of a granulate which contains only one and not several different active substances, wherein the active ingredient is preferably a pharmaceutical active substance.
  • the active substance is preferably used in the granulation process with an average particle size (a volume-related distribution, in the following abbreviated only by the average particle size) of less than 30 pm, more preferably an average particle size of less than 20 pm.
  • the active ingredient is used with an average particle size of 5 pm or more.
  • the above particle size distribution and thus the mean particle size is advantageously determined by light scattering methods, for example with the Horiba LA-950 Retsch Technology GmbH laser scattered light spectrometer, Haan, Germany.
  • the active ingredient is used with an average particle size of 5 pm or more.
  • a binder is used to produce a granule containing active ingredient.
  • Binder as a solid may e.g. may be mixed with drug particles, and this mixture may be introduced into the granulator, or the binder may be introduced into the granulator with the granulation fluid, e.g. is dissolved in the granulation liquid and then sprayed with the granulation liquid during the granulation process. The latter is preferred.
  • the concentration of the binder in the granulation fluid may be e.g. 5 wt .-% to 10 wt .-%, it is preferably 5 wt .-% or less.
  • the binder and the binder concentration should be selected so that caking on the fan during the granulation process is reduced or prevented.
  • % figures below refer to percent by weight. The inventors have found that it is possible to work with high spray rates for the granulation liquid in the process according to the invention for the production of an active ingredient-containing granules and, nevertheless, well-rounded granules can be obtained with little substance loss, ie good yield.
  • the process according to the invention for producing an active ingredient-containing granulate is therefore characterized in that active ingredient particles, at least one binder and preferably at least one flow agent are introduced into the granulator and the granulation liquid is sprayed in the range from 80 g / min to 120 g / is sprayed min.
  • the introduction of the binder into the granulator is preferably carried out with the granulating liquid containing the binder e.g. in dissolved form.
  • the invention also relates to a process for the preparation of granules comprising non-water-soluble or sparingly water-soluble active ingredients.
  • Water-soluble may e.g. be defined so that for dissolving a part by weight of the water-soluble substance 100 or less, preferably 30 or less parts by volume of water at 25 ° C are needed.
  • an aqueous granulation fluid is preferably used.
  • a nonaqueous solvent such as ethanol or isopropanol, may be used.
  • an active ingredient-containing granulate after the beginning of the granulation process no active substance is introduced into the granulation process in solid form.
  • no Active substance in solid form is distributed over existing larger active ingredient particles or forming aggregates during the granulation process via a nozzle (eg powder-layering method). This allows a simpler implementation of the method and a less expensive granulation apparatus.
  • a binder and only one active substance are used in the process for the preparation of an active ingredient-containing granulate and that this active ingredient is a pharmaceutical active substance which is used in a unimodal particle size distribution.
  • no MCC is used in the process according to the invention for producing a granule containing active ingredient.
  • no further granulation auxiliaries are used in addition to the binder and the optional flow agent for the production of granules and / or pellets according to the invention.
  • MCC and no substitute for MCC such as kaolin or bentonite is used.
  • substitutes for MCC which are preferably used for the inventive production of granules and / or pellets at most in an amount of 5 wt .-% or less in the produced granules or pellets are chitosan, low-substituted hydroxypropyl cellulose (low-substituted hydroxypropylcellulose , L-HPC), glyceryl monostearate (GMS), polyacrylic acids (carbopol resins), starch and starch derivatives, cellulose powder (powdered cellulose), cross-linked polyvinylpyrrolidone (crospovidone), kappa (K) -carrageenan, hydroxypropylmethylcellulose (HPMC) and hydroxyethylcellulose (HEC) , Polyethylene oxide (PEO) with methoxypolyethylene glycol (MPEG) pectic acid and / or enzyme-resistant starch type III.
  • PEO polyethylene oxide
  • MPEG methoxypolyethylene glycol
  • a difficulty in the production of granules in the rotor granulator is that in the good bed sufficient moisture must be adjusted in order to achieve a high sphericity of the granules.
  • the moisture can also lead to losses of active substance due to adhesion to surfaces such as filters, container walls or the floor, which is designed as a fan in the method described here. Drying these adhesions can make them rough surfaces on which built-up particles can rub off. Abrasion and detachment of the material during the drying phase can in turn lead to higher fines content and thus wider particle size distributions.
  • the moisture content is thus of particular interest for the formation of granules of the desired size and with the desired properties, and it is advantageous to control the moisture content throughout the entire production process.
  • the measurement In order to be able to determine the moisture content during the process in the process space (in-line), the measurement must be able to take place quickly and the good must not be destroyed by the measurement. Suitable methods are NIR spectroscopy (near-infrared spectroscopy) and the microwave resonance method. Moisture determination is indirect in both methods. So it is not the humidity directly but determines a correlated with the moisture property of the estate.
  • the sample In the microwave resonance method, the sample is placed in a very weak microwave resonant field. The field is changed by the sample and from this change the moisture content of the sample is determined. As this is an indirect method for determining moisture, it is calibrated against a reference humidity, which is determined via a direct method for measuring moisture (eg loss of drying measurement). Representative samples can be used to determine a correlation function, which is then used to calculate the moisture content (Kappes, R; Grimm, C; Scholz, J; Moisture measurement from laboratory to process, Pharm. Ind. 72 (7), pp.1231 - 1238, 2010).
  • the present application therefore also relates to a process for the preparation of an active ingredient-containing granules, wherein the method comprises introducing at least one active ingredient and optionally one or more excipients as material to be moved into the granulator and granulated using a granulation liquid as the treatment medium wherein the spraying of the granulation liquid is interrupted in each case when a predefined moisture content is exceeded. The spraying of the granulation liquid is thus interrupted several times in this process.
  • the material By stopping the Granulations remplikeitszudostechnik and optionally increasing the amount of air (eg up to 550 m 3 -h "1 ), the material can be dried until the particles separate and adjusts a uniform, spiral-shaped Gutiolo.Then more Granulationsbaukeit can be added. These cycles can last as long be repeated until the desired particle size (eg 355-1000 ⁇ ) is reached. Then, the dosing of the granulation liquid can be finally stopped and the material can be dried in the same apparatus, or pellets can be prepared by spraying the formed granules with a solvent for the active ingredient or with an active-ingredient-containing liquid and subsequent drying (see below).
  • the granules or pellets according to the invention can be dried to a desired degree of drying after preparation in the granulator. Unless otherwise expressly stated or obvious from the context, drying takes place in the granulator until the product has a suitable residual moisture content, e.g. of ⁇ 10%, in particular ⁇ > 7.5%, more preferably ⁇ 5% and most preferably ⁇ 2.5%. Unless otherwise expressly stated or obvious from the context, all values given here for describing the product refer to the ready-to-use product after drying. Unless stated otherwise,% data describing the product refer to the respective end product without solvent used.
  • the process according to the invention for the production of an active ingredient-containing granulate by means of wet granulation preferably relates to a process wherein the granulate contains 5% by weight or less of microcrystalline cellulose, preferably 2% by weight or less and most preferably no microcrystalline cellulose, and an active substance content of 80 Wt% or more, preferably 85 wt% or more, or 90 wt% or more, or 92 wt% or more.
  • the moisture content of such mixtures to be granulated is particularly critical in order to avoid losses due to adhesion to surfaces during the manufacturing process.
  • the moisture content rises rapidly until the powder to be granulated begins to stick to the container walls and to the sensor.
  • the metered addition of the preferably binder-containing granulation liquid is then interrupted until the powder dissolves from the surfaces and then restarted.
  • the moisture curve here has corresponding humidity maxima and minima. In these cycles, it is moved until the powder begins to granulate. This can e.g. when performing the process by observing the process, sample draw and / or measurement of drying loss are determined with simultaneous MW-moisture measurement.
  • the MW humidities can be determined during the entire humidification phase in which the granulation liquid is sprayed with interruptions.
  • the change in the moisture content during the course of the process can be monitored on the basis of the MW moisture measurements, which can be used for process control.
  • the process may e.g. can be interrupted when certain MW-moisture levels are exceeded or the metering of the granulation liquid for the entire process can be terminated by the time at which the MW-moisture is reached, was previously determined that the powder begins to granulate.
  • Adhesions on the container wall and thus also on the sensor can be detected promptly with the microwave resonance sensor system and it can be reacted accordingly (eg by interrupting the spraying of the granulation liquid). In this way, solid buildup, which can not be removed during the course of the process and can lead to undesirable abrasion of formed particles during drying, be avoided efficiently.
  • the calculated microwave moisture may be used next to or instead of the visual assessment to determine the end point of the wetting phase, ie the phase in which the granulation liquid is sprayed (intermittently).
  • the manufacturing process and the product quality of granules or pellets can be influenced by the speed of the fan.
  • the speed of rotation of the fan is preferably chosen so that a uniform, spiral-shaped material movement is established.
  • the speed can e.g. in the range of 9 to 20 Hz.
  • the process according to the invention for producing a granule containing active ingredient is also distinguished by the fact that the yield of granules of the sieve fraction 355-1000 ⁇ 55 wt .-% or more, preferably 65 wt .-% or more, especially 70 wt. % or more of the theory, and preferably no MCC is used.
  • the method according to the invention for producing a granule containing active ingredient is characterized in that the yield of granules of the sieve fraction 355-1000 pm 65 wt .-% or more, in particular 70 wt .-% or more based on the weight of the ready-to-use product is.
  • the present invention is directed to the granules obtainable by a process according to the invention for producing a granule containing active ingredient.
  • the present application also discloses a granulate obtainable by a process according to the invention for producing a granule containing active ingredient, the granules having an average particle size in the range from 50 ⁇ m to 1000 ⁇ m, preferably from 355 ⁇ m to 800 ⁇ m, and most preferably from 400 ⁇ m up to 700 pm.
  • the particle size distribution is given in terms of volume and is determined by means of image analysis, the volume of the distribution being determined by the well-known algorithms Image analysis software is determined.
  • the particle size is evaluated as the shortest (x c min ) of all measured maximum chords (x c ) of the particle projection.
  • the granules have an average sphericity in the range of 0.90 and 1.00 and the sphericity is determined by image analysis as follows
  • a sphericity in the range of 0.90 and 1.00 corresponds to a good roundness of the particle.
  • a perfect sphere has a sphericity (SPHT value) of 1.
  • a sample is placed on a conveyor trough via a funnel. The channel doses the particles into a measuring shaft.
  • the groove is controlled so that the particle density in the camera recording area is 1%.
  • the particles While the particles fall vertically through the measuring well into a collecting vessel, they are photographed by the digital cameras at a take-up rate of 60 images per second. The resulting images are then scanned in 64 spatial directions. Perimeter and area are counted by the pixels of the images. The mean sphericity is given in terms of volume, the volume of the distribution being determined by well-known algorithms from the image analysis software. The basis of definition for the measured quantities is DIN 66141.
  • the granules according to the invention are granules whose granules of the sieve fraction 355-1000 pm have an average sphericity in the range from 0.90 to 1.00 and the sphericity is determined as described above.
  • the granules according to the invention may also be granules in one embodiment, the granules having an average B / L value in the range from 0.80 to 1.00, preferably in the range from 0.80 to 1.00 Range of 0.833 and 1.00, and the B / L value is determined by image analysis as follows
  • the B / L value indicates the minimum ratio of two Feret diameters (Fe1 and Fe2) standing perpendicular to each other (particle width to particle length ratio).
  • the average B / L value is given by volume, the volume of the distribution being determined by well-known algorithms from the image analysis software.
  • the granules according to the invention are granules whose granules of the sieve fraction 355-1000 ⁇ m have an average B / L value in the range of 0.80 and 1.00, preferably in the range of 0.833 and 1.00, and the B / L value is determined as described above.
  • the granules preferably have a particle size distribution with a fürgangsummenquantil d10, which is 200 ⁇ or greater and with a fürgangsummenquantil d90, which is 800 ⁇ or less.
  • the particle size distribution should be as narrow as possible.
  • the sum of the passing sum, based on the total volume, indicates the volume fraction of the particles smaller than d.
  • the present invention is in one embodiment also directed to a granulate obtainable by a process according to the invention for producing a granule containing active ingredient, wherein the granules are at least 66 wt .-%, more preferably at least 80 Wt .-%, and most preferably at least 85 wt .-% consists of active ingredient.
  • the granules comprise at least 90% by weight of active ingredient and in another embodiment even at least 92% by weight.
  • the granule of the present invention is preferably a granule whose granules have an average breaking strength of 1.50 MPa or more, more preferably 2.00 MPa or more, and most preferably 2.25 MPa or more. Preference is further given to a granulate whose granules of the sieve fraction 355-1000 m have an average breaking strength of 1.50 MPa or more, more preferably 2.00 MPa or more, and most preferably 2.25 MPa or more.
  • the breaking strength can be determined as described in Example 1.
  • the granules comprise at least one active ingredient, optionally several active ingredients. It is preferred that the granules comprise at least one active ingredient and one binder. Preferably, the granules comprise only one and not several active ingredients. In another embodiment, the granules of an active ingredient, a binder and optionally one or more other adjuvants.
  • the granule contains a binder
  • it is preferably a binder selected from the group consisting of ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), starch, modified starch, methylcellulose (MC) , Hydroxyethyl cellulose (HEC), ethyl hydroxyethyl cellulose (EHEC), sodium carboxymethyl cellulose (Na-CMC), alginates, tragacanth, polyvinyl acetate, polyvinyl alcohol, bentonite, veegum, gelatin, maltodextrin, sucrose and glucose.
  • EC ethylcellulose
  • HPC hydroxypropylcellulose
  • CMC carboxymethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • PVP polyvinylpyrrolidone
  • MC methylcellulose
  • HEC Hydroxyethy
  • the granulate according to the invention preferably contains a binder which decomposes above a certain temperature, ie a binder which does not have any actual melting temperature.
  • the granules of the invention contain from 0.1 to 10 wt%, preferably from 0.1 to 8 wt% and most preferably from 0.1 to 5 wt%.
  • the granules contain less than 5% by weight or less than 2% by weight of a binder having a melting temperature in the range of 40 ° C and 100 ° C.
  • Binder with such a melting temperature in the range of 40 ° C and 100 ° C are typically used in melt granulation processes and not in wet granulation processes. Therefore, the granules according to the invention preferably contain no binder with a melting temperature in the range of 40 ° C and 100 ° C.
  • the binder contained in the granules contains no polyethylene glycol and no glycerol monostearate.
  • the granules contain hydroxypropylmethylcellulose as a binder. Hydroxypropylmethylcelluloses can be defined, for example, as nonionic cellulose ethers having average molecular weights of 10,000 to 50,000.
  • the viscosities of the 2% strength aqueous solutions are, for example, between 3 mPas and 30,000 mPas.
  • HPMC a low-viscosity HPMC of substitution type 2910 (proportion of methoxy 28-30%, hydroxypropoxy 7-12%) having a viscosity of 3 mPas (2.4-3.6 mPas) is preferred (see eg Pharmacoat Certificate of Analysis 2010).
  • the mass fraction of active ingredient: binder in the granules is preferably in the range of 10: 1 and 30: 1, more preferably in the range of 15: 1 and 25: 1, most preferably about 20: 1.
  • the granules can of course in addition to binder and active ingredient include other substances, eg Auxiliaries which improve the flowability of the active ingredient, such as Silica.
  • the granules should contain less than 20% by weight MCC, in a further embodiment at most 10% by weight MCC. Preference is given to granules which contain no MCC.
  • the granules contain no basic inorganic salts and no dilute alkali metal hydroxide.
  • the granules and thus the granules may comprise, in addition to binder and active ingredient, other substances, for example adjuvants which improve the fluidity of the active substance, such as silica or talc.
  • the granules comprise flow agent particles.
  • the flow agent particles typically have an average particle size of less than 10 ⁇ to 20 ⁇ .
  • both hydrophobic and non-hydrophobic superplasticizers can be used.
  • the flux particles do not dissolve during the granulation process and do not or only slightly swell during the granulation process.
  • the fluid particles can swell.
  • nonhydrophobic flow agents is preferred, for example, so that the drug release is not delayed by the flow agent.
  • the lowest possible flow additive is preferred.
  • the release of the active ingredient from the granules may be further promoted by the fact that the granules produced by the method of the invention typically have one or more non-uniformly distributed voids (such as air inclusions) which are capable of inhibiting the release of the active agent, respectively. to influence the disintegration of the granules or of the pellets formed therefrom.
  • Very small cavities are not suitable.
  • the cavities of the granules are typically non-elongated and have no clear geometric shape.
  • the cavities have z. B. a diameter of 10 ⁇ in or more, or 20 ⁇ or more, or 40 ⁇ or more in its longest extent.
  • the granules of the granules according to the invention may have cavities with a diameter of 50 ⁇ m or more, or 60 ⁇ m or more in their longest extent.
  • the granules according to the invention relate to granules, wherein the granules comprise flow agent particles and / or have one or more cavities.
  • the present invention also relates to a process for the production of pellets.
  • This process comprises spraying an active ingredient-containing granulate according to the invention with a solvent for the active substance or with a liquid, the granulate and the liquid comprising the same active ingredient, whereby an active-ingredient-containing outer region forms on the granules, the pellets being 80% by weight or more active ingredient based on the total pellet weight; and wherein the mass ratio of the drug contained in the granules to the drug present in the exterior is in the range of 1: 1 to 20: 1.
  • a solvent for the active ingredient may, for example, be understood as meaning an agent which requires 100 or less, preferably 30 or fewer, parts by volume of solvent to dissolve 1 part by weight of the active substance.
  • pellets with a very high active ingredient content can be produced without having to apply a thick coating layer to the core-forming granule in lengthy process steps in order to produce pellets with good roundness and with a very high active ingredient content.
  • the granules used to prepare the pellets according to the invention may contain, for example, at least 50% by weight, preferably at least 66% by weight, more preferably at least 80% by weight of active ingredient, based on the total amount of active ingredient in the resulting pellets.
  • the weight fraction of the granules used based on the total weight of the pellets obtainable by spraying an active ingredient-containing granules according to the invention with a liquid containing active substance, it is possible, for example, to produce pellets in which the granules used account for at least 50% by weight, preferably at least 75% by weight on the total weight of the pellets.
  • the granules used are already round.
  • the active ingredient content can be further increased and the roundness of the particles can be improved if necessary.
  • the duration of the manufacturing process can be kept low because no thick coating layer is necessary to ultimately obtain pellets with good roundness.
  • the pellets according to the invention and also the granules produced by wet granulation usually have a smooth surface.
  • an outer region is typically formed, which differs from the granules used forming the core, so that pellets are formed which form a granule forming the core of the pellet forms and having a granule applied to the coating layer.
  • the pellets according to the invention can in some cases be obtained by spraying active ingredient-containing granules with water which is free of active ingredient.
  • a non-aqueous solvent such as, for example, ethanol or isopropanol, may be used to spray the granules to produce the pellets according to the invention, which contains the active ingredient in dissolved form.
  • the heavy water-soluble or non-water-soluble active ingredient may be suspended in water. In this case, the addition of a binder may be required to obtain the pellets according to the invention.
  • Water-soluble binders are preferably used both in the production of granules and in the production of pellets, if the binders are used in the respective processes.
  • the granules according to the invention and / or the pellets according to the invention preferably consist of a water-soluble active substance, a water-soluble binder and, if present, a non-hydrophobic flow agent. Purely aqueous granulate production processes or pellet production processes are preferred according to the invention.
  • the granules according to the invention and / or the pellets according to the invention consist of a sparingly water-soluble or non-water-soluble active ingredient, a water-soluble binder and, if present, a nonhydrophobic flow agent.
  • the granulation liquid of the granulation process and the liquid used for spraying in the pellet production comprise the same solvent, or that the granulation liquid of the granulation process comprises the solvent used for pelletizing spraying.
  • the granulation fluid may be e.g. preferably consist of a particular solvent, which may also contain binders, and the liquid used for spraying may consist of the same solvent, which optionally also comprises active ingredient.
  • a solvent in which the active ingredient at least partially dissolves can improve the roundness and strength of the pellets, and is therefore advantageous.
  • step a preparation of the granules (step a) and the spraying with a solvent for the active ingredient contained in the granules or with a liquid containing active substance (step b) can be carried out successively in the same granulator without between the two steps. a cleaning must be done.
  • the inventive method for the production of pellets thus also relates to a method wherein the spraying of the granules is carried out as a moving material with the solvent or the liquid as a treatment medium in the granulator in which the granules were prepared.
  • the granulator has previously been described in connection with the process according to the invention for producing a granule containing active ingredient.
  • the moisture content in this phase of spraying the granules with solvent or the liquid does not change significantly, which can be recognized as a plateau in the moisture curve (rounding-out phase).
  • the moisture content can be kept here in a predetermined range.
  • the speed of the fan of the apparatus may be used to dry the pellets. can be reduced and the amount of air can be increased if necessary.
  • a granulate according to the invention is produced, the process comprising introducing at least one active ingredient and optionally one or more excipients into the granulator as the material to be agitated and using a granulation liquid as Granulated treatment medium, wherein the spraying of the granulation liquid is interrupted in each case when a predefined Gutfeuchte is exceeded and then (b) the resulting active ingredient-containing granules with a solvent for the active ingredient or with a liquid comprising the same active ingredient as the granules, sprayed, wherein the spraying of the granules is carried out as a material to be moved with the solvent or the liquid as a treatment medium in the granulator in which the granules were prepared, and is then dried, good pellet yields can be achieved.
  • a granulator is preferably a device such as in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 and / or 15
  • the invention therefore includes e.g. also a process for the preparation of pellets, wherein the yield of pellets of the sieve fraction 355-1000 ⁇ 55 wt .-% or more, preferably 65 wt .-% or more, in particular 70 wt .-% or more of theory, and preferably no MCC is used.
  • the inventive method for the production of pellets is characterized in that the yield of pellets of the sieve fraction 355-1000 ⁇ 65 wt .-% or more, in particular 70 wt .-% or more based on the weight of the ready to use product ,
  • the pellets of the invention are characterized by a volume-based particle size distribution with a moderator d10, which is 200 ⁇ or greater, and with a moderator d90, which is 800 ⁇ or less.
  • the present invention also relates in a further aspect to pellets obtainable by a process according to the invention for the production of pellets.
  • pellets can be produced whose outer region or active substance-containing coating layer differs structurally and / or materially from the rest of the pellet.
  • Pellets available, wherein the mass ratio of the active ingredient contained in the granules to the active substance present in the outer region in the range of 1, 5: 1 to 20: 1, preferably in the range of 2: 1 to 10: 1, more preferably in the range of 3: 1 to 8: 1 and most preferably in the range of 4: 1 to 6: 1.
  • the cladding layer of the pellets is thin and therefore not always readily recognizable with optical aids. In the context of the present invention, therefore, is also spoken of "outside of the pellet".
  • the outer region or the cladding layer may, for example, have a thickness of less than 50 ⁇ m, preferably less than 20 ⁇ m, for example 6-12 ⁇ m. If desired, for example, by prolonged spraying of the granules according to the invention with a liquid containing active substance, but also a thicker outer area can be produced in order to further improve the spherical shape of the pellets.
  • the outside area is formed by spraying the granules with a liquid (solvent for the active substance contained in the granules or liquid containing the same active ingredient as the granules) and not as the granules by wet granulation of active ingredient particles.
  • a liquid solvent for the active substance contained in the granules or liquid containing the same active ingredient as the granules
  • the outside area of the pellets according to the invention has a different structure than the granules used.
  • the outer area formed by spraying can have a more or less regular, repetitive or symmetrical structure, be denser and contain fewer, or at best only very small or no voids or air inclusions.
  • the outdoor area therefore has in many cases a greater density than the Granule used. If the outdoor area exceptionally contains one or more cavities, these are due to the process elongated and / or rather flat and not like the cavities of Granule without definable geometry.
  • the outer region of the pellets formed by spraying the granules with a liquid can at least partially surround the granules used, respectively. envelop, in some embodiments also completely.
  • spraying the granules forms a cladding layer which covers the entire granule surface.
  • the liquid used for spraying preferably contains at least one active ingredient, it may also contain several active ingredients. Preferably, it contains only one and not several active ingredients.
  • the outer region typically formed by spraying the granules may also differ materially from the granules used.
  • the liquid used for spraying which preferably contains active substance
  • contains no binder since in the granulation (ie in the preparation of the granules) almost always a binder is used.
  • the active ingredient-containing liquid contains typically no binder.
  • the liquid used for spraying which preferably contains active ingredient
  • typically contains no flow agent typically contains no flow agent.
  • the granulation process and the subsequent spraying with the liquid, which preferably contains active ingredient can take place in the same granulator without intermediate cleaning, it can not be ruled out that a few flow agent particles are located in or even on the outside.
  • the proportion of active ingredient in the outer region formed by the spraying of the granules or the coating layer of the pellet according to the invention is typically greater than the active ingredient content in the granule.
  • the exterior of the pellets so produced consists of nearly 100% by weight of active ingredient.
  • the outer area of the pellets formed by the spraying of the granules consists of e.g. at least 90% by weight of active ingredient.
  • the outer region is at least 85% by weight or at least 95% by weight, preferably at least 98% by weight of active ingredient.
  • the structural and / or material characteristics of the exterior area formed by the spraying of the granules can also help to obtain pellets with sufficient breaking strength.
  • cavities resp. Air inclusions can have a negative effect on the breaking strength
  • cavities resp. Air pockets according to the invention quite desirable because they can promote the disintegration of the pellets at the destination (stomach, intestine, etc.) and thus the release of the drug.
  • MCC is added to the granulation only to increase the plasticity of Gutmasse in order to obtain round granules, acts on a limited basis but also as a binder. In very high proportions of MCC can be quite different in some cases Binders are dispensed with.
  • the addition of MCC in the amounts taught by the prior art ie at least 20 wt .-% or at least 30 wt .-%) affects the release of the active ingredient in some cases considerably, which, for example, on the formation of a swollen non-soluble matrix or Drug adsorption to MCC can be attributed.
  • the release of the active substance immediately after reaching the destination can be further promoted and / or accelerated by using a liquid for spraying the granules, preferably a solution containing active substance which does not comprise a binder and preferably also no other auxiliaries.
  • Pellets in which the outer area is free of binder can have a particularly favorable release behavior, since a binder can delay the release of the active ingredient.
  • the release of the active ingredient is further promoted by the fact that the pellets of the invention are relatively small due to the lack of starter cores. For the same amount of active ingredient small pellets have a larger surface area than large pellets, which accelerates the release of the active ingredient.
  • a flux contained in the granules promotes the release of the active ingredient. This effect is particularly noticeable when the flux particles swell when they reach their destination or when the flux particles otherwise affect the stability of the granules.
  • the flow agent particles are typically particles that are significantly smaller than the granules.
  • the invention relates to pellets wherein the pellets contain less than 5% by weight, preferably less than 2% by weight of a binder having a melting temperature in the range of 40 ° C and 100 ° C, based on the total pellet weight.
  • the pellet according to the invention contains no binder with a melting temperature in the range of 40 ° C and 100 ° C.
  • the invention also relates to pellets wherein the pellets have an average sphericity in the range 0.90 to 1.00 and the sphericity is determined by image analysis as follows
  • the invention relates to pellets, wherein the pellets of the sieve fraction 355-1000 ⁇ m have an average sphericity in the range from 0.90 to 1.00 and the sphericity is determined as described above.
  • the invention relates to pellets wherein the pellets have an average B / L value in the range of 0.80 and 1.00, preferably in the range of 0.833 and 1.00, and the B / L value as follows by image analysis is determined
  • the measurement of the B / L value can be carried out as described above, the average B / L value of the pellets being determined here instead of the average B / L value of the granules (see above).
  • the invention relates to pellets, wherein the pellets of the sieve fraction 355- 1000 ⁇ ⁇ ⁇ an average B / L value in the range of 0.80 and 1, 00, preferably in the range of 0.833 and 1 having 00, and the B / L value is determined as described above.
  • the pellets of the present invention may, for example, have an average particle size in the range from 50 m to 1000 ⁇ m, preferably in the range from 355 ⁇ m to 800 ⁇ m, and most preferably in the range from 400 ⁇ m to 700 ⁇ m, the particle size being determinable as described above is.
  • W average particle size in the range from 50 m to 1000 ⁇ m, preferably in the range from 355 ⁇ m to 800 ⁇ m, and most preferably in the range from 400 ⁇ m to 700 ⁇ m, the particle size being determinable as described above is.
  • pellets according to the invention are obtainable by a process comprising spraying active ingredient-containing granules with a liquid, which typically forms a coating layer, it is clear that no active substance-free layer is applied between the granules and the coating layer.
  • the pellets according to the invention have a high breaking strength.
  • the pellets of the present invention especially the pellets of the sieve fraction 355-1000 ⁇ , have an average breaking strength of 1.50 MPa or more, more preferably 2.00 MPa or more, and most preferably 2.25 MPa or more. In one embodiment, the pellets have an average crush strength of 3.00 MPa or more.
  • the breaking strength can be determined as described in Example 1.
  • a low porosity of the pellets may also be advantageous in order to obtain pellets containing high-active content.
  • the present invention therefore also relates in one embodiment to low porosity pellets.
  • the pellets contain at least 80% by weight or at least 85% by weight of active ingredient, preferably at least 89% by weight or at least 90% by weight of active ingredient, more preferably at least 91% by weight or at least 92% by weight of active ingredient, and most preferably at least 93% by weight of active ingredient, based in each case on the total pellet weight.
  • the pellets according to the invention may comprise one or more excipients.
  • the pellets comprise auxiliaries, it is preferred according to the invention that the pellets do not comprise microcrystalline cellulose (MCC).
  • the active ingredient contained in the pellet is an orally administered drug, especially an orally administered pharmaceutical drug.
  • the present application relates to pellets obtainable by a method comprising spraying a granule containing an oral drug with a drug-containing fluid comprising the same orally-administered drug.
  • the pellet comprises several orally administered drugs.
  • the pellets of the present invention may e.g. an active substance selected from the group consisting of sulpiride, meclofenoxate, piracetam, acetylsalicylic acid, diflunisal, naproxen, paracetamol, phenazone, propyphenazone, metamizole, carbamazepine, oxcarbazepine, valproic acid, primidone, vigabatrin, mesuximide, ethosuximide, carbutamide, tolbutamide, quinidine, tocainide, dicloxacillin, flucloxacillin, ampicillin, amoxicillin, cefuroxime, cefotiam hexetil, cefalexin, cefaclor, cefadroxil, cefuroxime axetil, cefetamet, erythromycin, spiramycin A, ciprofloxacin, metronidazole, nimorazole, tinid
  • the active ingredient is preferably not vitamin C or ibuprofen.
  • the pellets of the present invention have a high content of active ingredient, it is particularly appropriate to produce pellets according to the invention with such active ingredients that must be taken in high dosages.
  • active ingredients which have to be taken in daily or single doses of> 1 g.
  • the pellets comprise an active ingredient which must be taken at daily or single doses of at least 450 mg, preferably at least 500 mg, and most preferably at least 1 g.
  • the preparation / availability of smaller tablets which may contain the pellets of the invention facilitates oral administration and thereby improves patient compliance. Accordingly, such small tablets are also beneficial for lower dose drugs.
  • the pellets of the invention also include an active ingredient that must be taken at daily or single doses of less than 450 mg.
  • the pellets include an agent having an influence on bone structure and mineralization, such as strontium ranelate.
  • the pellets comprise an intestinal antiphlogistic, e.g. 5-aminosalicylic acid (mesalazine) or a similar agent.
  • intestinal antiphlogistic e.g. 5-aminosalicylic acid (mesalazine) or a similar agent.
  • the pellets comprise an antiepileptic such as levetiracetam or carbamazepine or a carboxamide derivative such as e.g. Oxcarbazepine.
  • an antiepileptic such as levetiracetam or carbamazepine or a carboxamide derivative such as e.g. Oxcarbazepine.
  • the pellets comprise a non-steroidal anti-inflammatory drug or anti-inflammatory drug such as anti-inflammatory drug.
  • a fenamate for example mefenamic acid
  • a propionic acid derivative for example ibuprofen
  • the pellets comprise an antibiotic such as linezolid or moxifloxacin.
  • the pellets comprise a psycholeptic, in particular an antipsychotic, e.g. a diazepine, oxazepine and thiazepine, especially quetiapine.
  • a psycholeptic in particular an antipsychotic, e.g. a diazepine, oxazepine and thiazepine, especially quetiapine.
  • the pellets comprise an antiviral agent for systemic use, in particular nucleosides and nucleotides such as valganciclovir.
  • the pellets comprise an agent for treating hyperkalaemia and hyperphosphatemia, such as sevelamer or lanthanum (III) carbonate.
  • the pellets comprise an analgesic or an antipyretic, in particular salicylic acid or a salicylic acid derivative such as, for example, acetylsalicylic acid.
  • the pellets comprise a vitamin such as ascorbic acid or pyridoxine.
  • the pellets comprise a mucolytic, such as acetylcysteine.
  • the pellets include a cardiac or an agent that is used systemically in obstructive pulmonary disease, such as theophylline.
  • the pellets comprise a Caicium channel blocker, in particular a selective Caiciumkanalblocker primarily cardiac action such as a benzothiazepine derivative (for example diltiazem) or a phenylalkylamine derivatives (for example verapamil).
  • a Caicium channel blocker in particular a selective Caiciumkanalblocker primarily cardiac action such as a benzothiazepine derivative (for example diltiazem) or a phenylalkylamine derivatives (for example verapamil).
  • the pellets comprise a beta adrenoreceptor antagonist, particularly a selective beta adrenoceptor antagonist such as metoprolol.
  • the pellets comprise an agent for use in peptic ulcer or gastroesophageal reflux disease, especially a histamine H2 receptor antagonist such as cimetidine or ranitidine.
  • the pellets comprise an antidiabetic agent, in particular a biguanide such as metformin.
  • the pellets comprise an agent acting on the renin-angiotensin system, in particular a pure angiotensin II antagonist such as valsartan or irbesartan.
  • the pellets comprise a cardiac agent such as ranolazine.
  • the list of active ingredients contained in the present specification is not exhaustive.
  • the list of active ingredients included in the present specification includes the corresponding pharmaceutically acceptable salts, respectively.
  • the pellets of the present invention comprise metoprolol or its salts.
  • the pellets of the present invention comprise metoprolol succinate.
  • coated pellets which have, from the inside to the outside, a granule on which an active substance-containing outer area has been formed by spraying and optionally one or more coatings, the first of these coatings being applied to the active substance-containing outer area of the pellet.
  • the present invention therefore also relates to a process for producing coated pellets, comprising spraying pellets according to the invention with a coating liquid, wherein the spraying of the pellets according to the invention is carried out as a material to be moved with the coating liquid as the treatment medium in the granulator in which the granules are produced and in which the pellets according to the invention were produced.
  • the granulator has previously been described in connection with the process according to the invention for producing a granule containing active ingredient.
  • the invention thus relates to a process which comprises, in a step (a) in the granulator described, first producing an active ingredient-containing granulate according to the invention, which then in a step (b) with a solvent for the active ingredient contained in the granules or is sprayed with a liquid containing active substance. After drying the pellets in the described granulator, the coating liquid is then sprayed onto the pellets in a step (c) in the granulator and coated pellets are thereby produced. Preferably, at least a partial purification of the granulator takes place before carrying out step (c).
  • the described granulator is therefore suitable for that all process steps in the same apparatus can be carried out without modification.
  • the high coating efficiency achieved with the process according to the invention for the production of coated pellets also means that the cleaning of the interior of the apparatus after completion of the coating is much easier and correspondingly takes less time. This is particularly important because the pilling and coating can be carried out in the same apparatus, i. After completion of the coating, the apparatus should be available as soon as possible for the granulation of the subsequent batch.
  • Coating efficiency is a parameter for process-related material loss and can be calculated as the ratio of measured (weight gain measured, wg m ) to theoretical ⁇ weight gain theoretical, wg t ) mass increase (Obara S, Maruyama N, Nishiyama Y, Kokubo H; Dry coating: an innovative enteric coating method using a cellulose derivative; Eur J Pharm Biopharm 47, 51-59 (1999); Tobiska S; Examination and modeling of coating processes on the Bohle Laboratory Coater BLC5; Dissertation, Martin Luther University of Halle-Wittenberg (2002); Pearnchob N, Bodmeier R; Dry polymer powder coating and comparison with conventional liquid-based coatings for Eudragit- "RS, ethylcellulose and shellac; Eur J Pharm Biopharm 56, 363-369 (2003)).
  • the theoretical mass increase may be e.g. be defined as the solids content of the applied dispersion.
  • the measured mass increase is determined by subtracting the respective amount of starter material (mass of the pellets to be coated) from the actually determined weight (each taking into account the drying loss).
  • Coated pellets according to the invention may, for example, have the following structure from the inside to the outside: a granule on which an active substance-containing outer region has been formed, and a coating which contains no active substance is applied. It is possible to apply coatings to the pellets according to the invention which cause, for example, a taste masking of the active substance present in the granule and in the coating layer, or coatings which bring about a controlled release of the active substance contained in the granules and in the outer region.
  • the aforementioned coatings preferably contain no active ingredient. It is also possible, for example, to apply enteric coatings.
  • the coating liquid may be an Eudragit dispersion.
  • a dispersion comprising an anionic methacrylic acid-ethyl acrylate-1: 1 copolymer which dissolves from a pH of 5.5 (eg available as Eudragit L30-D55) can be used.
  • the minimum film-forming temperature can be lowered by addition of plasticizer (eg triethyl citrate). Because of the high sphericity of the pellets according to the invention, a uniform thickness of the coating layer can be achieved and little material is consumed. If desired, can be applied over such a coating again an effective off-containing layer.
  • the pellets or granules or coated pellets according to the invention can be used in medicaments or in diagnostic or nutritional supplements. For this it is advantageous to fill the pellets, coated pellets or granules in capsules or in stickpacks, or to compress them in MUPS tablets. Due to the high sphericity of the (coated) pellets and granules according to the invention and their good flowability and, preferably, high breaking strength associated therewith, the filling and processability are particularly simple.
  • the present invention therefore also relates, in one aspect, to a medicament, preferably in the form of a capsule, MUPS tablet or a stickpack containing a multiplicity of coated pellets according to the invention, a large number of pellets according to the invention or a granulate according to the invention.
  • Example 1 illustrates the invention:
  • the particle size distribution was determined using the Horiba LA-950 laser scattered light spectrometer (Retsch Technology GmbH, Haan). Metoprolol succinate was suspended and the particle size was measured by flow cell.
  • the Mie theory was used (according to ISO 13320-1 (1999) or European Pharmacopoeia 7.0 Monograph 2.9.31). As dispersing medium thin liquid paraffin was chosen because metoprolol succinate does not dissolve in it. It was measured at a transmission of 80-90%. For dispersion during the measurement, the circulation was adjusted to 8 and the stirrer to 7.
  • This mixture was sprayed discontinuously in the rotor granulator as described in claims 1-9 or FIG. 6 in DE 10 2010 052 312.7 (FIG. 5 of the present application) with the granulating liquid of water and Pharmacoat® 603 (5%) ( For parameters, see Table 3, "Humidifying").
  • the static distributor bottom was replaced by a corresponding rotor in a Ventilus® 25 device.
  • the metering in of the granulation liquid was interrupted until the particles separated and a uniform, helical movement of the material took place. These cycles were repeatedly until the desired particle size was reached. In the present case, this corresponds to the spraying of the total quantity of granulation liquid as indicated in Table 1. This amount was determined in preliminary experiments.
  • the air volume and the speed of the fan were increased (parameter see Table 3 "Filleting").
  • the particles were sprayed with water or an aqueous solution of metoprolosuccinate.
  • batches A and B only water was sprayed.
  • Lot C-E the particles were sprayed with an aqueous solution of metoprolosuccinate (24.9% by weight).
  • the same spray nozzle was used for moistening and rounding.
  • the spray gap was set at 0.25 mm to prepare batches A-C and 0.15 mm for making batches D and E.
  • the spray pressure was 3.0 / 2.6 / 0.7 bar for batches A and B and 3.0 / 2.6 / 0.4 bar for batches C-E.
  • the information is given as the upper spray air / lower spray air / support air.
  • the drying took place after the rounding out in the same apparatus.
  • the liquid supply was stopped by spraying, reduces the speed of the fan to 9 Hz and increases the amount of air, if necessary.
  • the supply air temperature was not changed.
  • the weight indicates the actually determined weight of the product obtained.
  • a halogen dryer of the type MB 45 (OHAUS GmbH, Giessen). In each case 3 g of a sample were weighed and dried at 100 ° C to constant weight over 90 seconds. The drying loss was the moisture content of the sample in percent of
  • the sample was placed on a chute (width at the outlet side: 60 mm) via a funnel.
  • a control value of 65 was selected.
  • the gutter dosed the particles into the measuring well.
  • a starting value of 60 and a maximum control value of 75 were used.
  • the groove was controlled so that the particle density in the camera recording area was 1%.
  • the particles fell vertically into the receptacle through the well, they were photographed by the digital cameras at a rate of 60 frames per second. The resulting images were then scanned in 64 spatial directions. The particle size was evaluated as the shortest (x c min ) of all measured maximum chords x c of the particle projection.
  • the particle size distribution was reported on a volume basis, the volume of the distribution being determined according to generally known algorithms by the image analysis software.
  • the sum-of-passage quantiles d 10, d 50 and d 90 were given as mean and standard deviation over all measured particle projections of three measurements.
  • three samples of 5.0 g pellets were measured.
  • the roundness (sphericity, SPHT) of the particles was also evaluated on the basis of the image analysis performed with the Camsizer®.
  • the two-dimensional projection of each particle is scanned in 64 spatial directions. Perimeter and area are based on the pixels of the pictures.
  • the basis for defining the measurable quantities that can be calculated by the Camsizer® software is DIN 66141.
  • the ratio of the particle area to the circumference was used to assess the roundness of the particles.
  • the mean sphericity is given by volume, the volume of the distribution being determined by well-known algorithms from the image analysis software. Three measurements were carried out per batch with 5.0 g pellets each. The indicated SPHT value corresponds to the average of the three measurements.
  • the average B / L value is given by volume, with the volume of the distribution being determined by well-known algorithms from the image analysis software. For each batch, three measurements were carried out with 5.0 g pellets each. The specified B / L value is the mean of the three measurements.
  • the breaking force F was measured using the Texture Analyzer TA.XT plus (Stable Micro Systems, Ltd., Godalming, Great Britain).
  • the sample is positioned centrally under the measuring body on a flat surface.
  • the measuring body is mounted on a mechanically movable load cell and is lowered for force measurement at a constant speed over a given distance in the direction of the sample. After exceeding the release force force-displacement or force-time diagrams are recorded.
  • the breaking force F can then be determined as the maximum of the measuring curve.
  • the diameter d of the sample in the direction of fracture can be measured as the distance of the measuring body to the sample support surface at the time of exceeding the release force.
  • Breakage strength was calculated taking into account the spherical shape of the Shipway pellets (Shipway PH, Hutchings IM, Fracture of brittle spheres under compression and impact loading, I. Elastic stress distributions, Philos Mag A 67, 1389-1404 (1993), Telless M, Kleinebudde P; Properties of pellets manufactured by wet extrusion / spheronization process using kappa-carrageenan: effect of process parameters; AAPS PharmSciTech 8, E95 (2007)).
  • pellets were equilibrated at 25 ° C and 60% relative humidity prior to measurement.
  • Per batch 50 pellets of the sieve fraction 355-1000 ⁇ were measured individually (Groebel CA; Production of Pellets by Extrusion and Spheronization-Systematic Formulation Development as Basis for a Knowledge-Based System; Dissertation, Ruprecht-Karls-University Heidelberg (2004); T Subscribes M, Kleinebudde Use of kappa-carrageenan as an alternative pelletization aid to microcrystalline cellulose in extrusion / spheronisation II. Influence of drug and filiform type; Eur J Pharm Biopharm 63, 68-75 (2006)). Indicated is the mean of the measurements.
  • the measuring body used was a polished Plexiglas stamp with a diameter of 25 mm.
  • particles having a breaking strength of 1 MPa are generally suitable. Accordingly, all produced particles can be used for further processing.
  • the active ingredient content of 83.75% by weight could be increased to more than 90% by weight when using the method according to the invention.
  • the spraying with the granulation liquid is stopped as soon as active ingredient powder begins to settle on the inner wall of the granulator.
  • the moisture content decreases temporarily, whereby the thus initiated, short-term drying process begins mainly on the inner walls of the granulator, since there even after stopping the spraying process Process air is introduced.
  • the spraying of the granulation liquid can be continued until, in turn, active ingredient powder begins to settle on the inner wall of the granulator.
  • This discontinuous spraying is continued until the actual granulation process begins (see the maximum of the moisture curve in FIG. 6a).
  • the good moisture required for agglomeration is thus achieved in stages, as shown in FIG. 6a.
  • the measurements were carried out in-line with a microwave resonance sensor system (TB 4210-Ex, MW 4210-Ex) from Tews.
  • a microwave resonance sensor system (TB 4210-Ex, MW 4210-Ex) from Tews.
  • the temperature in the process room was measured in parallel via a PT 1000 sensor.
  • the measurement signals were recorded by the software Tews Moisture View ⁇ (TMV 2.0.0.52) and evaluated by correlation function.
  • the calibration of the microwave resonance signals took place against the loss of drying as reference moisture (FIG. 6b).
  • samples were drawn at defined times during the process and measured with the halogen dryer and a correlation function was calculated.
  • the determination was carried out with a halogen dryer from Ohaus. Each 3 g of sample were dried at 100 ° C to constant weight over 90 seconds. The drying loss was the moisture content of the sample in percent of the starting weight. Since the microwave resonance signals change substance-specifically, a specific calibration function was recorded for each recipe.
  • the microwave resonator permanently measures the attenuation and the resonant frequency shift of the microwave field to a 0 signal
  • the 0 signal was recorded before each process before filling the system. Then the measurement was started. Recorded measurement signals were from the software based on the deposited Correlation function directly converted into microwave moisture signals and displayed next to density and temperature values.
  • the calibration was chosen so that the maximum humidity value is easy to detect.
  • Air volume m3-h supply air temperature spray rate (g-min spray pressure

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Abstract

La présente invention concerne des pastilles contenant au moins un principe actif, ainsi qu'un procédé de production de pastilles et des médicaments contenant les pastilles selon l'invention. Ces pastilles s'obtiennent par pulvérisation de granules contenant le principe actif avec un solvant pour le principe actif ou avec un liquide contenant le principe actif.
PCT/EP2012/059196 2012-04-16 2012-05-16 Pastilles à teneur élevée en principe actif WO2013156088A1 (fr)

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EP12722352.7A EP2838514A1 (fr) 2012-04-16 2012-05-16 Pastilles à teneur élevée en principe actif

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DE102012007671A DE102012007671A1 (de) 2012-04-16 2012-04-16 Pellets mit hohem Wirkstoffgehalt
DE102012007671.1 2012-04-16

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WO2013156088A1 true WO2013156088A1 (fr) 2013-10-24

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DE102022106367A1 (de) * 2022-03-18 2023-09-21 Add Advanced Drug Delivery Technologies Ltd. Beschichtungsapparateeinheit und Verfahren zur Herstellung von mit einem Beschichtungsmittel funktional beschichteten Granulaten

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US11986554B2 (en) 2015-04-29 2024-05-21 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions

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